Immunochemical Analysis of Quinol-Thioether-Derived Covalent Protein Adducts in Rodent Species Sensitive and Resistant to Quinol-Thioether-Mediated Nephrotoxicity
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- 作者：Heather E. Kleiner ; Thomas W. Jones ; Terrence J. Monks ; and Serrine S. Lau
- 刊名：Chemical Research in Toxicology
- 出版年：1998
- 出版时间：November 1998
- 年：1998
- 卷：11
- 期：11
- 页码：1291 - 1300
- 全文大小：373K
- 年卷期：v.11,no.11(November 1998)
- ISSN：1520-5010
文摘
2,3,5-Tris(glutathion-S-yl)hydroquinone (TGHQ) is nephrotoxic in male Fischer 344 rats (20
f">mol/kg) and albino guinea pigs (200 f">mol/kg), but not BALB/c or B6C3F1 mice or GoldenSyrian hamsters (200 f">mol/kg). Since quinones are known to alkylate proteins, and becausesuch macromolecular damage may play a role in cytotoxicity, we investigated the covalentbinding of TGHQ to kidney (target tissue) and liver (nontarget tissue) of rodents "sensitive" or"resistant" to the nephrotoxic effects of TGHQ. Immunohistochemical staining of tissueobtained 2 h after administration of TGHQ, with rabbit anti-2-bromo-N-(acetyl-L-cystein-S-yl)HQ antibodies, correlated with the subsequent region of necrosis observed 19 h after dosingin Fischer 344 rats and guinea pigs. Immunohistochemical staining was localized to the S3segment of the renal proximal tubules, at the corticomedullary junction along the medullaryrays, and in the outer stripe of the outer medulla. Immunostaining was also observed in thesame region in hamsters, but subsequent necrosis did not develop. In contrast, no immunostaining was observed in mice. Moreover, immunostaining was not detected in the livers ofany species. Western blot analysis revealed numerous immunoreactive renal proteins in TGHQ-treated animals. The most distinctive immunostaining renal proteins were observed in Fischer344 rats at ~34 kDa (mitochondria), ~35 kDa (nuclei) which comigrated with histone H1, and~73 kDa (urine) which comigrated with 
fchars/gamma.gif" BORDER=0 >-glutamyl transpeptidase. These adducted proteinswere not detected in other species. Qualitative differences in alkylated proteins may thereforecontribute to species susceptibility to TGHQ.
f">mol/kg) and albino guinea pigs (200 f">mol/kg), but not BALB/c or B6C3F1 mice or GoldenSyrian hamsters (200 f">mol/kg). Since quinones are known to alkylate proteins, and becausesuch macromolecular damage may play a role in cytotoxicity, we investigated the covalentbinding of TGHQ to kidney (target tissue) and liver (nontarget tissue) of rodents "sensitive" or"resistant" to the nephrotoxic effects of TGHQ. Immunohistochemical staining of tissueobtained 2 h after administration of TGHQ, with rabbit anti-2-bromo-N-(acetyl-L-cystein-S-yl)HQ antibodies, correlated with the subsequent region of necrosis observed 19 h after dosingin Fischer 344 rats and guinea pigs. Immunohistochemical staining was localized to the S3segment of the renal proximal tubules, at the corticomedullary junction along the medullaryrays, and in the outer stripe of the outer medulla. Immunostaining was also observed in thesame region in hamsters, but subsequent necrosis did not develop. In contrast, no immunostaining was observed in mice. Moreover, immunostaining was not detected in the livers ofany species. Western blot analysis revealed numerous immunoreactive renal proteins in TGHQ-treated animals. The most distinctive immunostaining renal proteins were observed in Fischer344 rats at ~34 kDa (mitochondria), ~35 kDa (nuclei) which comigrated with histone H1, and~73 kDa (urine) which comigrated with fchars/gamma.gif" BORDER=0 >-glutamyl transpeptidase. These adducted proteinswere not detected in other species. Qualitative differences in alkylated proteins may thereforecontribute to species susceptibility to TGHQ.